Amides, preparation and therapeutic use as modulators of CCR-receptor activity

ABSTRACT

The invention provides compounds of general formula (I), wherein R 1 , X, Y, n, R 2 , Z 1 , Z 2 , A 1 , A 2 , Q, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , t and R 16  are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small Secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved fourcysteine motif. The chemokine superfamily can be divided into two maingroups exhibiting characteristic structural motifs, the Cys-X-Cys(C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basisof a single amino acid insertion between the NH-proximal pair ofcysteine residues and sequence similarity.

The C-X-C chemolines include several potent chemoattractants andactivators of neutrophils such as interleulin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those previously mentioned.

In accordance with the present invention, there is therefore provided acompound of general formula

wherein

-   -   R¹ represents a saturated or unsaturated 5- to 10-membered        heterocyclic ring system comprising at least one ring heteroatom        selected from nitrogen, oxygen and sulphur, the ring system        being optionally substituted by one or more substituents        independently selected from halogen, cyano, nitro, carboxyl,        hydroxyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl and —C(O)NR¹¹R¹²;    -   X represents an oxygen or sulphur atom or a CH₂, CH(CH₃), OCH₂,        CH₂O, CH₂NH, NH or carbonyl group and Y represents a nitrogen        atom or a CH or C(OH) group, provided that when X represents an        oxygen or sulphur atom or a CH₂O, CH₂NH or NH group, then Y        represents a CH group;    -   n is 0, 1 or 2;    -   each R² independently represents a C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, —CH₂OH or carboxyl group;    -   Z¹ represents a bond or a group (CH₂)_(q) where q is 1 or 2;    -   Z² represents a bond or a group CH₂, with the proviso that Z¹        and Z² do not both simultaneously represent a bond;    -   when Y represents a nitrogen atom, then A¹ represents CH and A²        represents NH, or A¹ represents a nitrogen atom and A²        represents CH₂, or A¹ represents a nitrogen atom and A²        represents a bond; or when Y represents a group CH or C(OH),        then A¹ represents a nitrogen atom and A² represents a bond;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R³ represents —NHC(O)R¹³ or —C(O)NR¹⁴R¹⁵;    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4- to 7-membered saturated        carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and        R⁴ and R⁸ together with the carbon atoms to which they are        attached form a 5- to 6-membered saturated carbocycle;    -   R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4- to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group;    -   R¹³ represents a group C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆        cycloalkyl, adamantyl, C₅-C₆ cycloalkenyl, phenyl or a saturated        or unsaturated 5- to 10-membered heterocyclic ring system        comprising at least one ring heteroatom selected from nitrogen,        oxygen and sulphur, each of which may be optionally substituted        by one or more substituents independently selected from nitro,        hydroxyl, oxo, halogen, carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,        phenyl and —NHC(O)—R¹⁷;    -   R¹⁴ and R¹⁵ each independently represent (i) a hydrogen        atom, (ii) a 5- to 6-membered saturated or unsaturated ring        optionally comprising at least one ring heteroatom selected from        nitrogen, oxygen and sulphur, the ring being optionally        substituted with at least one substituent selected from halogen,        methyl and trifluoromethyl, or (iii) a C₁-C₆ alkyl group        optionally substituted by at least one substituent selected from        halogen, trifluoromethyl, carboxyl, C₁-C₆ alkoxycarbonyl and a        5- to 6-membered saturated or unsaturated ring optionally        comprising at least one ring heteroatom selected from nitrogen,        oxygen and sulphur, the ring being optionally substituted with        at least one substituent selected from halogen, methyl and        trifluoromethyl, or    -   R¹⁴ and R¹⁵ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocycle;    -   t is 0, 1, 2 or 3;    -   each R¹⁶ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁸R¹⁹,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl, —C(O)NR²⁰R²¹, —NR²²C(O)(NH)_(v)R²³, phenyl, or        C₁-C₆ alkyl optionally substituted by at least one substituent        selected from carboxyl and C₁-C₆ alkoxycarbonyl;    -   R¹⁷ represents a C₁-C₆ alkyl, amino (—NH₂) or phenyl group;    -   R¹⁸ and R¹⁹ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R¹⁸ and R¹⁹ together with the nitrogen        atom to which they are attached form a 4- to 7-membered        saturated heterocycle;    -   R²⁰ and R²¹ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   v is 0 or 1;    -   R²² represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R²³ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by at least one substituent selected from        carboxyl, C₁-C₆ alkoxy and C₁-C₆ alkoxycarbonyl; or a        pharmaceutically a(eptable sait or solvate thereof.

In the context of the present specification, an alkyl or alkenylsubstituent group or an alkyl moiety in a substituent group may belinear or branched. A haloalkyl or haloalkoxy substituent group willcomprise at least one halogen atom, e.g. one, two, three or four halogenatoms. When R⁹ and R¹⁰ (or R¹⁴ and R¹⁵, or R¹⁸ and R¹⁹) represent a 4-to 7-membered saturated heterocycle, it should be understood that theonly heteroatom present is the nitrogen atom to which R⁹ and R¹⁰ (or R¹⁴and R¹⁵, or R¹⁸ and R¹⁹) are attached. In the definitions of each of R¹and R¹³, it should be noted that the saturated or unsaturated 5- to10-membered heterocyclic ring system may have alicyclic or aromaticproperties.

Similarly, in the definition of R¹⁴ and R¹⁵, a 5- to 6-memberedsaturated or unsaturated ring optionally comprising at least one ringheteroatom may have alicyclic or aromatic properties.

R¹ represents a saturated or unsaturated 5- to 10-membered heterocyclicring system comprising at least one ring heteroatom (e.g. one, two,three or four ring heteroatoms) selected from nitrogen, oxygen andsulphur, the ring system being optionally substituted by one or more(e.g. one, two, three or four) substituents independently selected fromhalogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro,carboxyl, hydroxyl, C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl), C₃-C₆ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl), C₁-C₆, preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy,n-propoxy or n-butoxy), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalllyl(e.g. trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), —NR⁹R¹⁰, C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl) or—C(O)NR¹¹R¹².

The saturated or unsaturated 5- to 10-membered heterocyclic ring systemmay be monocyclic or polycyclic (e.g. bicyclic) and comprises up to fourring heteroatoms independently selected fiom nitrogen, oxygen andsulphur. Examples of ring systems that may be used include pyrrolidinyl,piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl,thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl,benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.

In an embodiment of the invention, R¹ represents an unsaturated 5- to6-membered heterocyclic ring system comprising at least one ringnitrogen atom, the ring system being optionally substituted by one ormore halogen atoms.

In an embodiment of the invention, X represents an oxygen atom or a CH₂,OCH₂, CH₂O, NH or carbonyl group.

In another embodiment of the invention, Y represents a nitrogen atom orCH group.

Preferred combinations of X—Y include O—CH, OCH₂—CH, NH—CH, CH₂O—CH,CH₂—N, C(O)—N and CH₂—CH.

Preferred combinations of Y, Z¹ and Z² include:

Y Z¹ Z² CH CH₂ bond CH bond CH₂ CH CH₂ CH₂ CH (CH₂)₂ bond N CH₂ CH₂

Each R² independently represents a C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), —CH₂OH or carboxyl group. In anembodiment of the invention, n is 1 and R² represents a methyl,methoxycarbonyl, ethoxycarbonyl, —CH₂OH or carboxyl group.

In an embodiment of the invention, Q represents an oxygen atom.

R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R⁴, R⁵, R⁶ andR⁷ together represent a C₁-C₄ alkylene chain linking the two carbonatoms to which they are attached to form a 4- to 7-membered saturatedcarbocycle (e.g. cyclopentyl or cyclohexyl), or R⁵, R⁶ and R⁷ eachrepresent a hydrogen atom and R⁴ and R⁸ together with the carbon atomsto which they are attached form a 5- to 6-membered saturated carbocycle(particularly cyclopentyl).

R⁸ represents a hydrogen atom, a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) or is linked to R⁴ as defined above.

R⁹ and R¹⁰ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle (e.g. pyrrolidinyl or piperidinyl).

R¹¹ and R¹² each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R¹³ represents a group C₁-C₆, preferably C₁-C₅, alkyl group (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), C₂-C₆, preferably C₂-C₄, alkenyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), adamantyl, C₅-C₆cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-memberedheterocyclic ring system comprising at least one ring heteroatom (e.g.one, two, three or four ring heteroatoms) selected from nitrogen, oxygenand sulphur, each of which (i.e. each of the recited groups and the ringsystem) may be optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from nitro, hydroxyl,oxo, halogen (e.g. fluorine, chlorine, bromine or iodine), carboxyl,C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio), C₁-C₆,preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonylor n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), phenyl and —NHC(O)—R¹⁷.

In R¹³, the saturated or unsaturated 5- to 10-membered heterocyclic ringsystem may be monocyclic or polycyclic (e.g. bicyclic) and comprises upto four ring heteroatoms independently selected from nitrogen, oxygenand sulphur. Examples of ring systems that may be used includepyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl,isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl,quinolinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.

In an embodiment of the invention, R¹³ represents a group C₁-C₆ alkyl,phenyl or a saturated or unsaturated 5- to 6-membered heterocyclic ringsystem comprising at least one ring heteroatom (e.g. one or two ringheteroatoms independently) selected from nitrogen, oxygen and sulphur,each of which may be optionally substituted by one, two, three or foursubstituents independently selected from nitro, hydroxyl, oxo, halogen,carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, phenyl and —NHC(O)—R¹⁷.

In another embodiment of the invention, R¹³ represents a group C₁-C₆alkyl, phenyl or an unsaturated 5- to 6-membered heterocyclic ringsystem comprising at least one ring heteroatom (e.g. one or two ringheteroatoms independently) selected from nitrogen and oxygen, each ofwhich may be optionally substituted by one or two substituentsindependently selected from halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy.

R¹⁴ and R¹⁵ each independently represent (i) a hydrogen atom, (ii) a 5-to 6-membered saturated or unsaturated ring optionally comprising atleast one ring heteroatom (e.g. one, two or three ring heteroatomsindependently) selected from nitrogen, oxygen and sulphur (examples ofrings include cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, thienyl and furanyl), the ringbeing optionally substituted with at least one substituent (e.g. one,two or three substituents independently) selected from halogen (e.g.fluorine, chlorine, bromine or iodine), methyl and trifluoromethyl, or(iii) a C₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)optionally substituted by at least one substituent (e.g. one, two orthree substituents independently) selected from halogen (e.g. fluorine,chlorine, bromine or iodine), trifluoromethyl, carboxyl, C₁-C₆,preferably C₁-C₄, alkoxycarbonyl and a 5- to 6-membered saturated orunsaturated ring optionally comprising at least one ring heteroatom(e.g. one, two or three ring heteroatoms independently) selected fromnitrogen, oxygen and sulphur (examples of rings include cyclopentyl,cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, thienyl and furanyl), the ring being optionally substitutedwith at least one substituent (e.g. one, two or three substituentsindependently) selected from halogen (e.g. fluorine, chlorine, bromineor iodine), methyl and trifluoromethyl, or R¹⁴ and R¹⁵ together with thenitrogen atom to which they are attached form a 4- to 7-memberedsaturated heterocycle (e.g. pyrrolidinyl or piperidinyl).

In an embodiment of the invention, R¹⁴ and R¹⁵ each independentlyrepresent a hydrogen atom or an unsubstituted C₁-C₆ alkyl group.

Each R¹⁶ independently represents halogen (e.g. chlorine, fluorine,bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), —NR¹⁸R¹⁹, C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR²⁰R²¹,—NR²²C(O)—(NH)_(v)R²³, phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) optionally substituted by at least one substituent(e.g. one, two or three substituents) independently selected fromcarboxyl and C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl).

In an embodiment of the invention, each R¹⁶ independently representshalogen, hydroxyl, cyano, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, C₁-C₄haloalkyl, C₁-C₄ alkylcarbonyl, phenyl or C₁-C₄ alkyl.

R¹⁷ represents a C₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl), amino or phenyl group.

R¹⁸ and R¹⁹ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R¹⁸ and R¹⁹together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle (e.g. pyrrolidinyl or piperidinyl).

R²⁰ and R²¹ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionallysubstituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonyl substituentgroup.

R²² represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl).

R²³ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least onesubstituent (e.g. one, two or three substituents independently) selectedfrom carboxyl, C₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferablyC₁-C₄, alkoxycarbonyl.

Examples of compounds of the invention include:

-   -   N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)        phenyl]benzamide,    -   N-[2-(3-{3-[(5-Chloro-2-pyridinyl)oxy)]-1-pyrrolidinyl}-2-hydroxypropoxy}-6-fluorophenyl]acetamide,    -   N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-phenyl]acetamide    -   N-[2-[(2S)-3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4        -fluorophenyl]acetamide,    -   N-[2-[(2R)-3-(3-[(5-Chloro-2-pyridinyl)oxy-]1-pyrrolidinyl)-2-hydroxypropoxy)-4        -fluorophenyl]acetamide,    -   N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-phenyl]3,5-dimethyl-1H-pyrrole-2-carboxyamide,    -   N-[2-(3-(3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)        phenyl]benzamide,    -   N-[2-[(2S)-3-3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4        -fluorophenyl]acetamide,    -   N-[2-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide,    -   N-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-6-fluoroph        enyl]acetamide,    -   N-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]acetamide,    -   N-[2-[(2S)-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4        -fluorophenyl]acetamide,    -   N-[2-[(2R)-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4        -fluorophenyl]acetamide,    -   N-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-phenyl]-3,5-diethyl-1H-pyffole-2-carboxyamide,    -   N-[2-(2-Hydroxy-3-{3-[(4-methyl-2-pyridinyl)oxy]-1-pyrrolidinyl}propoxy)        phenylbenzamide, and    -   N-{4-Fluoro-2-[((2S)2-hydroxy-3-{3-[(4-methyl-2-pyridinyl)oxy]-1-pyrrolidinyl}propyl)oxy]phenyl}acetamide.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above which comprises,

-   -   (a) reacting either a compound of general formula

wherein Y′ represents CH or C(OH) and R¹, X, n, R², Z¹ and Z² are asdefined in formula (I),or a compound of general formula

wherein A^(1′) represents CH and A^(2′) represents NH, or A^(1′)represents a nitrogen atom and A^(2′) represents CH₂ or a bond, Lrepresents a hydrogen atom or an activating group (e.g. Li) and R¹, X,n, R², Z¹ and Z² are as defined in formula (I),with a compound of general formula

wherein Q, R³, R⁴, R⁵, R⁶, R⁷, R⁸, t and R¹⁶ are as defined in formula(I); or

-   -   (b) reacting a compound of general formula

wherein R¹, X, Y, n, R², Z¹, Z², A¹, A², R⁴, R⁵, R⁶,R⁷ and R⁸ are asdefined in formula (I), with a compound of general formula

wherein L¹ represents a hydrogen atom or an activating group (e.g. Liwhen Q is CH₂) and Q, R³, t and R¹⁶ are as defined in formula (I); or

-   -   (c) when R³ represents —NHC(O)R¹³, reacting a compound of        general formula

wherein R¹, X, Y, n, R², Z¹, Z², A¹, A², Q, R⁴, R⁵, R⁶, R⁷, R⁸, t andR¹⁶ are as defined in formula (I), with a compound of general formula

wherein L² represents a leaving group (e.g. a hydroxyl group or ahalogen atom such as chlorine) and R¹³ is as defined in formula (I); or

-   -   (d) when R³ represents —C(O)NR¹⁴R¹⁵, reacting a compound of        general formula

wherein L³ represents a leaving group (e.g. a hydroxyl group or ahalogen atom such as chlorine) and R¹, X, Y, n, R², Z¹, Z², A¹, A², Q,R⁴, R⁵, R⁶, R⁷, R⁸, t and R¹⁶ are as defined in formula (I), with acompound of general formula (IX), NHR¹⁴R¹⁵, wherein

-   -   R¹⁴ and R¹⁵ are as defined in formula (I);    -   and optionally after (a), (b), (c) or (d) forming a        pharmaceutically acceptable salt or solvate of the compound of        formula (I) obtained.

The processes of the invention may conveniently be carried out in asolvent, e.g. an organic solvent such as an alcohol (e.g. methanol orethanol), a hydrocarbon (e.g. toluene) or tetrahydrofuran oracetonitrile at a temperature of, for example, 0° C. or above such as atemperature in the range from 0, 5, 10, 15 or 20° C. to 100, 110 or 120°C.

Compounds of formulae (II), (II′), (III), (IV), (V), (VI), (VII), (VIII)and (IX) are either commercially available, are well known in theliterature or may be prepared easily using known techniques.

It will be appreciated by those skilled in the art that in the processof the present invention certain fuinctional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theremoval of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers (including atropisomers) of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemoldne receptor (especially MIP-1αchemokine receptor) activity, and may be used in the treatment ofautoimmune, inflammatory, proliferative and hyperproliferative diseasesand immunologically-mediated diseases including rejection oftransplanted organs or tissues and Acquired Immunodeficiency Syndrome(AIDS).

Examples of these conditions are:

-   -   (1) (the respiratory tract) airways diseases including chronic        obstructive pulmonary disease (COPD) such as irreversible COPD;        asthma, such as bronchial, allergic, intrinsic, extrinsic and        dust asthma, particularly chronic or inveterate asthma (e.g.        late asthma and airways hyper-responsiveness); bronchitis;        acute, allergic, atrophic rhinitis and chronic rhinitis        including rhinitis caseosa, hypertrophic rhinitis, rhinitis        purulenta, rhinitis sicca and rhinitis medicamentosa; membranous        rhinitis including croupous, fibrinous and pseudomembranous        rhinitis and scrofoulous rhinitis; seasonal rhinitis including        rhinitis nervosa (hay fever) and vasomotor rhinitis;        sarcoidosis, farmer's lung and related diseases, fibroid lung        and idiopathic interstitial pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behcet's disease,        SJorgren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczematous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, erythemas, cutaneous        eosinophilias, uveitis, Alopecia areata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, food-related allergies which have effects        remote from the gut, e.g., migraine, rhinitis and eczema;    -   (5) (other tissues and systemic disease) multiple sclerosis,        atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),        lupus erythematosus, systemic lupus, erythematosus, Hashimoto's        thyroiditis, myasthenia gravis, type I diabetes, nephrotic        syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous        leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;    -   (6) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (7) cancers, especially non-small cell lung cancer (NSCLC) and        squamous sarcoma;    -   (8) diseases in which angiogenesis is associated with raised        chemokine levels; and    -   (9) cystic fibrosis, stroke, re-perfusion injury in the heart,        brain, peripheral limbs and sepsis.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating an inflammatory diseasewhich comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

The invention still further provides a method of treating an airwaysdisease which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I) may be in the range from 0.001 mg/kg to 30mg/kg.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (er cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention flrter provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e g. by oral admi,istration in the formof tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of solutions or suspensions; or bysubcutaneous administration; or by rectal administration in the form ofsuppositories; or transdermally.

The invention will now be further explained by reference to thefollowing illustrative examples, in which ¹H NMR spectra were recordedon Varian Unity Inova 400. The central solvent peak of chloroform-d(δ_(H) 7.27 ppm) were used as internal standard. Low resolution massspectra and accurate mass determination were recorded on aHewlett-Packard 1100 LC-MS system equipped with APCI/ESI ionizationchambers. All solvents and commercial reagents were laboratory grade andused as received. The nomenclature used for the compounds was generatedwith ACD/IUPAC Name Pro.

STARTING MATERIALS FOR EXAMPLES 1-16 Pyrrolidines

A) 5-Chloro-2-(3-pyrrolidinyloxy) pyridine

To a stirred solution of 5-chloro-2-pyridinol (323.9 mg; 2.5 mmol),tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (468.0 mg, 2.5 mmol) andtriphenylphosphine polymer bound (1 g, 3 mmol) in THF/CH₂Cl₂ (1:1, 5 ml)slowly was added diethyl azodicarboxylate (435.5 mg 2.5 mmol). Thesolution was slowly stirred overnight Resin was then removed byfiltration and washed with THF. The combined filtrates were evaporatedto dryness. The resulting residue was purified by RP-HPLC (10-40%CH₃CN). The pure material was treated with 95% TFA/5% H₂O, 30 min. TheTFA phase was then evaporated to give the desired product as a solid.

APCI-MS: m/z 199.1 [M⁺H⁺]

¹H-NMR(400 MHz, CDCl₃): δ 8.06(d, 1H), 7.57(m, 1H), 6.72(d, 1H), 5.60(m,1H), 3.63(m, 1H), 3.50(m, 3H), 2.32(m, 2H)

B) 5-Bromo-2-(3-pyrrolidinyloxy)pyridine

The title compound was prepared from of 5-bromo-2-pyridinol (435 mg; 2.5mmol), by a process analogous to that described in A) above.

APCI-MS: m/z 243.2 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 7.98(m, 1H), 7.54(m, 1H), 7.36(m, 1H), 5.3(m,1H), 3.62(m, 4H), 2.35(m, 2H).

C) 4-Methyl-2-(3-pyrrolidinyloxy)pyridine

The title compound was prepared from 4-methyl-2-pyridinol (273.0 mg; 2.5mmol), by a process analogous to that described in A) above.

APCI-MS: m/z 179.2 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 8.10(d, 1H), 7.06(m, 2H), 5.62(m, 1H),3.64(m, 2H), 3.52(m, 2H), 2.42(s, 3H), 2.40(m, 2H).

D) 2-Chloro-6-(3-pyrrolidinyloxy) pyridine

The title compound was prepared from 2-chloro-6-pyridinol by a processanalogous to that described in A) above.

¹H-NMR (400 MHz, CDCl₃): δ 7.50(m, 1H), 6.87(d, 1H), 6.63(d, 1H),5.47(m, 1H), 3.17(m, 1H), 3.13(m, 2H), 2.93(m, 1H), 2.15(m, 1H), 1,93(m,1H).

Epoxides

E) N-[2-Fluoro-6-(2-oxiranylmethoxy)phenyl]acetamide

i) 2-Amino-3-fluorophenol

To a stirred solution of 2,6-difluoronitrobenzene (1100 mg, 6.9 mmol) indry methanol (20 ml) was added a solution of sodium (180 mg, 7.8 mmol )in dry methanol (8 ml). The solution was stirred overnight. Afterconcentration water was added and the solution was extracted with ether,dried over MgSO₄, filtered and concentrated to a yellow residue (870mg.5.08 mmol). To the solution of the yellow residue in dichloromethane(10 ml) was added boron tribromide (1M in dichloromethane, 10 ml) andstirred at room temperature overnight. Water was then added and thesolution stirred for further 60 min. The organic phase was separated andthe water phase was extracted with ether. The combined organic phaseswere dried over MgSO₄, filtered and concentrated in vacuo to give abrownish residue. The residue was taken up into ether and washed with 2Msodium hydroxide and water. The water and sodium hydroxide washings werecombined and neutralized with 6M HCl and extracted with ether, driedover MgSO₄ and evaporated to give a yellow residue which was purified byflash chromatography on silica gel with EtOAc:Heptane; 1:3 as eluant togive the product (720 mg, 4.6 mmol) which was directly suspended withpalladium-charcoal (140 mg) in water-ethanol (30 ml). Sodium borohydride(530 mg) was added over a period of 5 minutes and the suspension wasstired at room temperature (1 h). The catalyst was removed by filtrationthrough a Celite pad The filtrate was acidified with 6M hydrochloricacid to destroy any residual borohydride, neutralized with 2M sodiumhydroxide, and then extracted with ether. The ethereal extracts weredried over MgSO₄ and evaporated.

APCI-MS: m/z 128.2 [M⁺H⁺]

ii) N-[2-Fluoro-6-(2-oxiranylmethoxy)phenyl]acetamide

To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) inwater-methanol (10 ml) acetic acid anhydride was added until all2-amino-3-fluorophenol was used. The solution was then concentrated to aresidue of N-(2-fluoro-6-tiydroxyphenyl) acetamide. To a mixture ofN-(2-fluoro-6-hydroxyphenyl) acetamide (399 mg, 2.36 mmol) and potassiumcarbonate (652 mg, 4.72 mmol) in DMF (5 ml) was added epibromohydrin(388 mg, 2.8 mmol) and was stirred at 70° C. for 3 hrs. Water and ethylacetate were added. the organic phase separated, dried and concentrated.The resulting residue was purified by RP-HPLC (10-40% CH₃CN ) to givethe desired product as a solid (242 mg, 1.08 mmol).

APCI-MS: m/z 226.2 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 7.15(m, 1H), 6.80(m, 2H), 6.70(d, 1H), 4.3(m,1H), 3.95(m, 1H), 3.3(m, 1H), 2.90(m, 1H), 2.75(m, 1H), 2.50(m, 1H),2.20(s, 3H)

F) 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid(2-oxiranylmethoxy-phenyl)-acetamide

i) 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid

To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich) (504mg, 3 mmol) in THF/H₂O/MeOH (5:1:1, 30 ml ) was added NaOH (480 mg, 12mmol) in H₂O (12 ml). The mixture was stirred at 75° C. overnight. Thehomogeneous mixture was washed with ether. To the aqueous layer wasadded a saturated aqueos KHSO₄ solution until the pH was about 3. Thesolution was then extracted with dichloromethane. The extracts weredried over MgSO₄ and evaporated. The residue was purified on silica(ethylacetate/methanol, 90/10) to give the title compound (375 mg, 90%).

¹H-NMR (400 MHz, CDCl₃): δ 8.75(s, 1H), 5.83(s, 1H), 2.25(s, 1H),2.38(s, 1H).

ii) 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-phenol)-acetamide

2-Aminophenol (545 mg 5 mmol), 3,5-dimethyl-1H-pyrrole-2-carboxylic acid(695 mg, 5 mmol) and HATU (1900 mg, 5 mmol) were stirred in DMF (20 ml).Diisopropylethylamine was added to pH 8. The mixture was stirredovernight and then concentrated. The residue was purified on RP-HPLC(acetonitrile/water, 10/90 to 40/60 with 0.5% trifluoroacetic acid) togive the title compound (550 mg, 48%).

APCI-MS: m/z 231.2 [M⁺H⁺]

¹H-NMR (400 MHz CDCl₃): δ 9.22(s, 1H); 7.63(s, 1H), 7.11(m, 2H), 7.03(m, 1H), 6.88(m, 1H), 5.88(s, 1H), 2.44(s, 1H), 2.24(s, 1H).

iii) 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid(2-oxiranylmethoxy-phenyl)-acetamide

The title compound was prepared from3,5-dimethyl-1H-pyrrole-2-carboxylic acid (2-phenol)-acetamide (ii) (300mg, 1.3 mmol) by a process analogous to that described in E ii) above.

APCI-MS: m/z 273.2 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 8.46(m, 1H), 8.31(m, 1H), 6;99(m, 2H),6.87(m, 1H), 5.85(m, 1H), 4.34(m, 1H), 3.92(m, 1H), 3.36(m, 1H), 2.91(m,2H), 2.71 (m, 1H), 2.47(m, 3H), 2.25(m, 3H)

G) N-[2-(2-Oxiranylmethoxy) phenyl]benzamide

To a strred solution of N-(2-hydroxy-phenyl)-benzamide (0.81 g, 3.80mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetonitrile wasadded epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reactionmixture was partitioned between dichloromethane and water. Afterevaporation of the organic solvent, the residue was crystallized frompetroleum ether and diethyl ether yielding the title compound (0.741 g,73%).

APCI-MS: m/z 227 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 8.65 (bs, 1H), 8.55 (bs, 1H), 7.94(d, 2H),7.53(m, 3H), 7.08 (bs, 2H), 6.96 (bs, 1H), 4.42(d, IH), 4.02, (m, IH),3.41 (bs, 1H), 2.96(s, 1H), (s, 1H).

H) N-4-Fluoro-2-[(2S) oxiranylmethoxy]phenyl)acetamide

(2S)-2-[(5-Fluoro-2-nitrophenoxy)methyl]oxirane (0.32 g, 1.5 mmol) wasdissolved in ethyl acetate (40 ml). Platinum on charcoal (0.15 g) wasadded, and the mixture was stirred in the atmosphere of hydrogen for 3hours at room temperature ard atmospheric pressure. The catalyst wasfiltered and washed on the filter with ethyl acetate (10 ml). Aceticanhydride (0.31 g, 0.28 ml, 3 mmol) and ethyl di(isopropyl)amine (0.39g, 0.52 ml, 3 mmol) were added to the solution. The reaction mixture wasstirred at room temperature for 3 hours, then washed with 1M NaOH (30ml) and brine (30 ml), and dried with Na₂SO₄. Evaporation of the solventand flash chromatography on silica gel with n-heptane/ethyl acetate(from 25 to 75%) afforded the titled compound (0.21 g, 0.92 mmol, 61%)as a colourless solid product.

APCI-MS: m/z 226 [M⁺H⁺]

¹H-NMR (400 MHz, CDCl₃): δ 8.30 (dd, 1H, J=5.2, J=9.0), 7.71 (br. S,1H), 8.6-8.8 (m, 2H), 436 (dd, 1H, J=2.3, J=11.3), 3.90 (dd, 1H, J=6.3,J=11.3), 3.40(m, 1H), 2.97 (t, 1H, J=4.4), 2.78 (dd, 1H, J=2.7, J=4.8),2.21(s, 3H).

I) N-(4-Fluoro-2-1(2R) oxiranylmethoxy]phenyl)acetamide

The title compound was prepared from(2R)-2-[(5-fluoro-2-nitrophenoxy)methyl]oxirane according to the methoddescribed in H) above.

EXAMPLE 1N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide

A solution of 5-chloro-2-(3-pyrrolidinyloxy) pyridine (100 μL,0.2M/DMSO), N-[2-(2-oxiranylmethoxy)phenyl]benzamide (100 μL, 0.2M/DMSO) was refluxed for 3 h.

APCI-MS: m/z 468.4 [M⁺H⁺]

The compounds of Examples 2 to 16 were prepared from the appropriatestarting materials described above by processes analogous to that ofExample 1 above.

EXAMPLE 2N-[2-3-{3-[(5-Chloro-2-pyridinyl)oxy)]-1-pyrrolidinyl)-}2-hydroxypropoxy}-6-fluorophenyl)acetamide

APCI-MS: m/z 424.3 [M⁺H⁺]

EXAMPLE 3N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-phenyl]acetamide

APCI-MS: m/z 406.3 [M⁺H⁺]

EXAMPLE 4N-[2-[(2S)-3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide

APCI-MS: m/z 424.3 [M⁺H⁺]

EXAMPLE 5N-[2-[(2R)-3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxrypropoxy)-4-fluorophenyl]acetamide

APCI-MS: m/z 424.3 [M⁺H⁺]

EXAMPLE 6N-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-phenyl]3,5-dimethyl-1-H-pyrrole-2-carboxyamide

APCI-MS: m/z 485.4 [M⁺H⁺]

EXAMPLE 7N-[2-3-(3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide APCI-MS: m/z 468.4 [M⁺H⁺] EXAMPLE 8N-[2-[(2S)-3-(3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide APCI-MS: m/z 424.3 M⁺H⁺] EXAMPLE 9N-[2-(3(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide

APCI-MS: m/z 512.3 [M⁺H⁺]

EXAMPLE 10N-[2-(3(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-6-fluorophenyl]acetamide

APCI-MS: m/z 468.3 [M⁺H⁺]

EXAMPLE 11N-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]acetamide

APCI-MS: m/z 450.3 [M⁺H⁺]

EXAMPLE 12N-[2-[(2S)-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide

APCI-MS: m/z 468.3 [M⁺H⁺]

EXAMPLE 13N-[2-[(2R)-3-(3-[(5Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide

APCI-MS: m/z 468.3 [M⁺H⁺]

EXAMPLE 14N-[2-(3-3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrroldinyl)-2-hydroxypropoxy)phenyl-]3,5-dimethyl-1H-pyrrole-2-carboxyamide

APCI-MS: m/z 529.4 [M⁺H⁺]

EXAMPLE 15N-[2-(2-Hydroxy-3-{3-[(4-methyl-2-pyridinyl)oxy]-1-pyrrolidinyl}propoxy)phenylbenzamide

APCI-MS: m/z 448.4 [M⁺H⁺]

EXAMPLE 16N-{4-Fluoro-2-[((2S)2-hydroxy-3-{3-[(4methyl-2-pyridinyl)oxy]-pyrrolidinyl}propyl)oxy]phenyl}acetamide

APCI-MS: m/z 404.4 [M⁺H⁺]

THP-1 Chemotaxis Assay

Introduction

The assay measured the chemotactic response elicited by MIP-1α chemokinein the human monocytic cell line THP-1. The compounds of the Exampleswere evaluated by their ability to depress the chemotactic response to astandard concentration of MIP-1α chemokine.

Methods

Culture of THP-1 Cells

Cells were thawed rapidly at 37° C. from frozen aliquots and resuspendedin a 25 cm flask containing 5 ml of RPMI-1640 medium supplemented withGlutamax and 10% heat inactivated fetal calf serum without antibiotics(RPMI+10% HIFCS). At day 3 the medium is discarded and replaced withfresh medium.

THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with10% heat inactivated fetal calf serum and glutarnax but withoutantibiotics. Optimal growth of the cells requires that they are passagedevery 3 days and that the minimum subculture density is 4×10+5 cells/ml.

Chemotaxis Assay

Cells were removed from the flask and washed by centrifgation inRPMI+10% HIFCS+glutamax. The cells were then resuspended at 2×10+7cells/ml in fresh medium (RPMI+10% HIFCS+glutamax) to which was addedcalcein-AM (5 μl of stock solution to 1 ml to give a final concentrationof 5×10⁻⁶ M). After gentle mixing the cells were incubated at 37° C. ina CO₂ incubator for 30 minutes. The cells were then diluted to 50 mlwith medium and washed twice by centrifugation at 400×g. Labelled cellswere then resuspended at a cell concentration of ×10+7 cells/nl andincubated with an equal volume of MIP-1α antagonist (10⁻¹⁰ M to 10⁻⁶ Mfinal concentration) for 30 minutes at 37° C. in a humidified CO₂incubator.

Chemotaxis was performed using Neuroprobe 96-well chemotaxis platesemploying 8 μm filters (cat no. 101-8). Thirty microlitres ofchemoattractant supplemented with various concentrations of antagonistsor vehicle were added to the lower wells of the plate in triplicate. Thefilter was then carefullly positioned on top and then 25 μl of cellspreincubated with the corresponding concentration of antagonist orvehicle were added to the surface of the filter. The plate was thenincubated for 2 hours at 37° C. in a humidified CO₂ incubator. The cellsremaining on the surface were then removed by adsorption and the wholeplate was centrifuged at 2000 rpm. for 10 minutes. The filter was thenremoved and the cells that had migrated to the lower wells werequantified by the fluorescence of cell associated calcein-AM. Cellmigration was then expressed in fluorescence units after subtraction ofthe reagent blank and values were standardized to % migration bycomparing the fluorescence values with that of a known number oflabelled cells. The effect of antagonists was calculated as % inhibitionwhen the number of migrated cells were compared with vehicle.

1. A compound of the following formula

wherein R¹ represents 2-pyridinyl being optionally substituted by one ormore substituents independently selected from halogen, cyano, nitro,carboxyl, hydroxyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsuiphonyl and —C(O)NR¹¹R¹²; X represents an oxygen or sulphur atom and Y represents a CH orC(OH) group; n is 0, 1 or 2; each R² independently represents a C₁-C₆alkyl, C₁-C₆ alkoxycarbonyl, —CH₂OH or carboxyl group; Z¹ represents abond or a group CH₂; Z² represents a bond or a group CH₂, with theproviso that Z¹ and Z² do not both simultaneously represent a bond orCH₂; A¹ represents a nitrogen atom and A² represents a bond; Qrepresents an oxygen or sulphur atom or a group CH₂ or NH; R³ represents—NHC(O)R¹³ or —C(O)NR¹⁴ R¹⁵; R⁴, R⁵, R⁶ and R⁷ each independentlyrepresent a hydrogen atom or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷together represent a C₁-C₄ alkylene chain linking the two carbon atomsto which they are attached to form a 4- to 7-membered saturatedcarbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and R⁴ andR⁸ together with the carbon atoms to which they are attached form a 5-to 6-membered saturated carbocycle; R⁸ represents a hydrogen atom, aC₁-C₆ alkyl group or is linked to R⁴ as defined above; R⁹ and R¹⁰ eachindependently represent a hydrogen atom or a C₁-C₆ alkyl group; R¹¹ andR¹² each independently represent a hydrogen atom or a C₁-C₆ alkyl group;R¹³ represents a group C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl,adamantyl, C₅-C₆ cycloalkenyl, or phenyl, each of which may beoptionally substituted by one or more substituents independentlyselected from nitro, hydroxyl, oxo, halogen, carboxyl, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, phenyl and —NHC(O)—R¹⁷; R¹⁴ and R¹⁵ each independentlyrepresent (i) a hydrogen atom, (ii) a 5- to 6-membered saturated orunsaturated cycloalkyl or phenyl ring optionally substituted with atleast one substituent selected from halogen, methyl and trifluoromethyl,or (iii) a C₁-C₆ alkyl group optionally substituted by at least onesubstituent selected from halogen, trifluoromethyl, carboxyl, C₁-C₆alkoxycarbonyl and a 5- to 6-membered saturated or unsaturatedcycloalkyl or phenyl ring optionally substituted with at least onesubstituent selected from halogen, methyl and trifluoromethyl; t is 0,1, 2 or 3; each R¹⁶ independently represents halogen, cyano, nitro,carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁸ R¹⁹, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆ alkylsulphonyl,—C(O)NR²⁰ R²¹, —NR²² C(O)(NH)_(v)R²³, phenyl, or C₁-C₆ alkyl optionallysubstituted by at least one substituent selected from carboxyl and C₁-C₆alkoxycarbonyl; R¹⁷ represents a C₁-C₆ alkyl, amino (—NH₂) or phenylgroup; R¹⁸ and R¹⁹ each independently represent a hydrogen atom or aC₁-C₆ alkyl group; R²⁰ and R²¹ each independently represent a hydrogenatom or a C₁-C₆ alkyl group optionally substituted by C₁-C₆alkoxycarbonyl; v is 0 or 1; R²² represents a hydrogen atom or a C₁-C₆alkyl group; and R²³ represents a hydrogen atom, or a C₁-C₆ alkyl groupoptionally substituted by at least one substituent selected fromcarboxyl, C₁-C₆ alkoxy and C₁-C₆ alkoxycarbonyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein Xrepresents O.
 3. A compound according to claim 1, wherein Y represents aCH group.
 4. A compound according to claim 1, wherein Q represents anoxygen atom.
 5. A compound according to claim 1, wherein R³ represents—NHC(O)R¹³ and R¹³ represents C₁-C₆ alkyl, or phenyl, each of which matbe optionally substituted by one, two, three or four substituentsindependently selected from nitro, hydroxyl, oxo, halogen, carboxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, phenyl and —NHC(O)-R¹⁷.
 6. A compound according to claim1 being:N-[2-(3-(3-[(5Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide, or N-[2-(3-{3-[(5-Chloro-2-pyridinyl)oxy)]-1-pyrrolidinyl}-2-hydroxypropoxy}-6-fluorophenyl)acetamide,orN-[2-(3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-[(2S)-3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-[(2R)-3-(3-[(5-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-(3-(3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide, orN-[2-[(2S)-3-(3-[(6-Chloro-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]benzamide,orN-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-6-fluorophenyl]acetamide,orN-[2-(3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)phenyl]acetamide,orN-[2-[(2S)-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-[(2R)-3-(3-[(5-Bromo-2-pyridinyl)oxy]-1-pyrrolidinyl)-2-hydroxypropoxy)-4-fluorophenyl]acetamide,orN-[2-(2-Hydroxy-3-{3-[(4-methyl-2-pyridinyl)oxy]-1-pyrrolidinyl}propoxy)phenylbenzamide, orN-{4-Fluoro-2-[((2S)2-hydroxy-3-{3-[(4-methyl-2-pyridinyl)oxy]-1-pyrrolidinyl}propyl)oxy]phenyl}acetamide.7. A process for the preparation of a compound of formula (I) as definedin claim 1 which comprises, (a) reacting either a compound of formula

wherein Y′ represents CH or C(OH) and R¹, X, n, R², Z¹ and Z² are asdefined in formula (I), or a compound of the following formula

wherein A^(1′) represents a nitrogen atom and A^(2′) represents CH₂ or abond, L represents a hydrogen atom or a lithium ion and R¹, X, n, R², Z¹and Z² are as defined in formula (I), with a compound of the followingformula

wherein Q, R³, R⁴, R⁵, R⁶, R⁷, R⁸, t and R¹⁶ are as defined in formula(I); or (b) reacting a compound of the following formula

wherein R¹, X, Y, n, R², Z¹, Z², A¹, A², R⁴, R⁵, R⁶, R⁷ and R⁸ areasdefined in formula (I), with a compound of the following formula

wherein L¹ represents a hydrogen atom or a lithium ion and Q, R³, t andR¹⁶ are as defined in formula (I); or (c) when R³ represents —NHC(O)R¹³,reacting a compound of the following formula

wherein R¹, X, Y, n, R², Z¹, Z², A¹, A², Q, R⁴, R⁵, R⁶, R⁷, R⁸, t andR¹⁶ areas defined in formula (I), with a compound of the followingformula

wherein L² represents a leaving group and R¹³ is as defined in formula(I); or (d) when R³ represents —C(O)NR¹⁴R¹⁵, reacting a compound of thefollowing formula

wherein L³ represents a leaving group and R¹, X, Y, n, R², Z¹, Z², A¹,A², Q, R⁴, R⁵, R⁶, R⁷, R⁸, t and R¹⁶ are as defined in formula (I), witha compound of general formula (IX), NHR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are asdefined in formula (I); and optionally after (a), (b), (c) or (d)forming a pharmaceutically acceptable salt of the compound of formula(I) obtained.
 8. A pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, as claimedin claim 1 association with a pharmaceutically acceptable adjuvant,diluent or carrier.